.beta.-Adrenoceptor blockers are widely used in the treatment of cardiovascular disease, including hypertension, angina pectoris, supraventricular arrhythmias, hypertrophic cardiomyopathy, and myocardial infarction. All these .beta.-adrenoceptor blockers share the common feature of being competitive antagonists of .beta.-adrenoceptor. They differ, however, in additional pharmacological properties, such as in the .beta..sub.1 -/.beta..sub.2 -selectivity, in the presence or absence of intrinsic sympathomimetic activity(ISA), in the membrane stabilizing activity, in the lipid versus water solubility is reported in Mount Sinai Journal of Medicine 52(7), 553, 1985(by Squire, A. et al.) and in the pharmacokinetic properties is reported in Arzneim-Forch/Drug Res. 36(1), 200, 1986 (by Harting, J. et al.). .beta.-adrenoceptor blockers with vasodilatory effects are also important for their calcium channel blocking properties as reported in Gen. Pharmacol. 24. 1425, 1993 (by inventor group).
The ultra short-acting .beta.-blocker(USABB) was described to be much safer than longer-acting antagonists in critically ill patients who require a .beta.-adrenoceptor antagonist is reported in Med. Chem. 25, 1402, 1982 (by Erhardt, P. W. et al.). This benefit is attributable to the fact that continuous infusion of USABB may achieve its steady-state concentrations quickly, and that the therapeutic actions terminate rapidly when the infusion is discontinued is reported in J. Pharm. Exp. Ther. 237, 912, 1986 (by Quon, C. Y. et al.). Esmolol (formula I), a .beta..sub.1 -selective adrenoceptor blocker rapidly metabolized by blood and liver esterase, was thus suggested for use as a USABB in controlling supraventricular arrhythmias, preoperative hypertension, and myocardial ischemia in acutely ill patients is reported in Drugs 33, 392, 1987 (by Benfield, P. et al.). USABB with vasodilatory properties was also of interest and seems to be of much greater significance than can be accounted for simply by .beta.-blockade alone is reported in Clin. Pharmacol. Ther. 38, 579, 1985 (by Reilly, C. S. et al.). Esterification of inactive metoprolol metabolite has shown various reduced and shorter duration systemic and .beta.-adrenergic blocking activities than metoprolol is reported by Bodor et al. 1988). Other esmolol-type, morpholino-type, and urea-type .beta.-blockers with USABB activities have also been reported recently in Chem. Pharm. Bull. 40, 1462, 1992 (by lguchi, S. H. et al.).
.beta.-Adrenoceptor blockers derived from vanilloid type compounds have been partly described in previous reports (by inventor group, 1993). Vanilloid type .beta.-blockers are a family of guaiacoxypropanolamines, chemically with 3-methoxy, 4-hydroxy benzyl nucleus that are found in pungent principles. Those vanilloid type compounds may cause the activation of sensory and autonomic cardiovascular system in vivo, but alkylation of its 4-hydroxy benzyl nucleus are devoid of pungent activity and maintain vasodilatory effect, there reported in Eur. J. Med. Chem. 27, 187, 1992 and 37, 938, 1994 (by inventor group). To date, very few .beta.-blockers with vanilloid base was described for its USABB activity (Iguchi, S. H. et al, 1992). The present study was further aimed at investigating the pharmacological properties of vasomolol, a derivative of vanillic acid or its ethyl ester with a vanilloid base, for its possible ability to bind to .beta.-adrenoceptors, its relative selectivity for .beta.-adrenoceptors, intrinsic sympathomimetic activity, and particularly its USABB and vasodilatory activities